Interpreting the clinical significance of combined variants in multiple recessive disease genes: Systematic investigation of Joubert Syndrome yields little support for oligogenicity

PURPOSE: Next generation sequencing (NGS) often identifies multiple rare predicted-deleterious variants (RDVs) in different genes associated with a recessive disorder in a given patient. Such variants have been proposed to contribute to digenicity/oligogenicity or “tri-allelism”, or to act as genetic modifiers. METHODS: Using the recessive ciliopathy Joubert syndrome (JBTS) as a model, we investigated these possibilities systematically, relying on NGS of known JBTS genes in a large JBTS and two control cohorts. RESULTS: 65% of affected individuals had a recessive genetic cause, while 4.9% were candidates for di-/oligogenicity, harboring heterozygous RDVs in ≥2 genes, compared to 4.2–8% in controls (p = 0.66–0.21). Based on ExAC allele frequencies, the probability of cumulating RDVs in any two JBTS genes is 9.3%. We found no support for “tri-allelism” as no unaffected siblings carried the same bi-allelic RDVs as their affected relative. 60% of individuals sharing identical causal RDVs displayed phenotypic discordance. While 38% of affected individuals harbored RDVs in addition to the causal mutations, their presence did not correlate with phenotypic severity. CONCLUSION: Our data offer little support for “tri-allelism” or digenicity/oligogenicity as clinically-relevant inheritance modes in JBTS. While phenotypic discordance supports the existence of genetic modifiers, identifying clinically-relevant modifiers remains challenging.